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Alzheimer's Disease Genetics
Genes play a complex and not yet fully understood role in all living things. Their part
in Alzheimer's disease (AD) is no exception. The more researchers learn about AD, the more
they become aware of the important function genes play in the development of AD. Recent
excitement has centered around the discovery of the relationship between the
apolipoprotein E (apoE) gene and AD.
Like recipes, genes provide instructions about how to make something, indicating what
ingredients go in and in what order. But, the environment (things outside the body like
food, the air we breathe, or chemicals we are exposed to) and processes inside the body
determine which ingredients are available and in what forms and quantities.
Along with environmental influences, genes and processes inside the body combine to do
more than just determine eye and hair color and other traits inherited from our parents.
For example, genes ensure that we have two hands and can use them to do things, like play
the piano. In almost every case, nature (genes) and nurture (including the physical and
chemical environment) work together to shape all living things.
Genes alone are not all-powerful. Most genes can do little until spurred on by other
substances. Although they are necessary in their own right, genes basically wait inside
the cell's nucleus (control center) for other molecules to come along and read their
Each of these messages is used to build a certain protein. Genes may build a protein
correctly or incorrectly, depending on the content of the DNA (deoxyribonucleic acid)
message. A gene can produce a faulty protein if it has one or more mutations (defects) in
its DNA. Faulty proteins can lead to cell malfunction, disease, and death.
[Illustration] Anatomy of Genes -- Shows a cell, mitochondria, the cell membrane, a
chromosome, the DNA double helix, DNA chains, linked sequence pairs of bases, paired
bases, and the four bases (cytosine, adenine, quanine, and thymine). Within the nucleus of
every human cell, two long, thread-like DNA strands encode the instructions for making all
proteins needed for life. Each cell holds more than 50,000 different genes found on 46
chromosomes of tightly coiled DNA. Each DNA strand bears four types of coding molecules or
bases. The sequence of bases in a gene is the code for making a protein.
Alzheimer's Disease: Not a Single-Gene Disorder
Diseases such as cystic fibrosis, muscular dystrophy, and Huntington's disease are
single-gene disorders. If a person inherits the gene that causes one of these disorders,
he or she surely will get the disease, unless it is prevented by other means. AD, on the
other hand, is not a single-gene disorder. More than one gene mutation can cause AD, and
genes on multiple chromosomes are involved. Sometimes, two genes--one from each
parent--are needed for a person to get the disorder.
The two basic types of AD are familial and sporadic. Familial AD (FAD) is a rare form
of AD, affecting less than 10 percent of AD patients. It is associated with gene mutations
on chromosomes 1, 14, and 21. FAD is the result of a certain inheritance pattern called
autosomal dominant. In this pattern, all offspring in the same generation have a 50/50
chance of developing AD if 1 of their parents had it. FAD occurs in younger people
(usually before age 60) than sporadic AD does.
ApoE in Sporadic Alzheimer's Disease
Sporadic AD usually occurs later in life, is far more common than FAD, and appears to
be related to the apoE gene found on chromosome 19. ApoE comes in several different forms
or alleles, but three occur most frequently. People inherit one allele (apoE2, apoE3, or
apoE4) of the apoE gene from each parent. People with both apoE3 and apoE4 alleles (E3/E4)
are affected by both alleles.
Having one or two copies of the E4 allele increases a person's risk of getting AD. That
is, having the E4 allele is a risk factor for AD. But, it does not mean that AD is
certain. Having one or two E4 alleles of the apoE gene increases a person's risk of AD,
but not to 100 percent. Some people with two copies of the E4 allele (the highest risk
group) have not developed the disease, and others with no E4s have. Scientists have yet to
determine the exact degree of risk of AD for any given person based on apoE status.
Medical tests are designed for various purposes. Some tests can indicate susceptibility
(the risk or likelihood of getting a disease); some help confirm diagnoses, and others
assist in planning or monitoring treatment. In an effort to prevent disease, physicians
test some people without symptoms to predict who might develop a given medical problem.
For people with AD symptoms, doctors try to rule out other disorders and determine, as
accurately as possible, what is causing the symptoms. If no other cause is found, AD is
A blood test is available to identify which apoE alleles a person has, because
apolipoprotein also is associated with an already well-studied condition, heart disease.
However, this blood test cannot tell people whether they will develop AD, or when. Instead
of a yes or no answer, the best information a person can get from this genetic assessment
for apoE is maybe or maybe not. Although some people want to know whether they will get AD
later in life, this type of prediction is not yet possible. In fact, some researchers
believe that apoE tests or other screening measures may never be able to predict AD with
100 percent accuracy.
In the research setting, apoE testing is a tool that can identify study volunteers who
may be at risk of getting AD. In this way, researchers can look for early brain changes.
This test also helps researchers compare the effectiveness of treatments for patients with
different apoE statuses. Several researchers believe that the apoE test is most useful for
studying AD risk in large groups of people and not for determining one person's individual
risk. Predictive screening in otherwise healthy people will be useful when effective ways
to treat or prevent AD are available.
Concerns About Confidentiality
ApoE testing, and indeed all genetic testing, raises ethical, legal, and social
questions for which we have few answers. ApoE information gathered for research purposes
generally can be protected by confidentiality laws. On the other hand, information
obtained in apoE testing may not be protected as confidential once it is part of a
person's medical records. Thereafter, employers, insurance companies, and other health
care organizations could gain access to this information; and discrimination could result.
For example, employment opportunities or insurance premiums could be affected.
Little is known about how stigma associated with an increased risk for AD may affect
people's families and their lives.
Public Policy on ApoE Testing
Scientists, ethicists, and other health professionals joined together in October of
1995 to write a public policy statement about the appropriateness of apoE testing and the
role of genetic counseling for AD. Discussions leading to the statement took place at a
conference in Chicago, Illinois, sponsored by the National Institute on Aging (NIA) and
the Alzheimer's Association.
The public policy statement supports the use of apoE testing for diagnostic purposes
only in conjunction with other tests during medical evaluations of patients who show AD
symptoms. It recommends not using apoE testing as a patient screening (predictive) method.
Conference participants said that further research and agreement about confidentiality are
needed before they will recommend routine apoE testing.
Depending on the study, research volunteers may have the opportunity, during genetic
counseling, to learn the results of their apoE testing. The meaning of these results is
complex. Since the results of apoE testing can be hard to understand, and more
importantly, devastating to those tested, the NIA and the Alzheimer's Association
recommend that research volunteers and their families receive genetic counseling before
and after testing.
People who learn through testing that they have an increased risk of getting AD may
experience emotional distress and depression about the future because there is no
effective way to prevent or cure the disease.
Through counseling, families can learn about the genetics of AD, the tests themselves,
and possible meanings of the results. Due to privacy, emotional, and health care issues,
the primary goal of genetic counseling is to help people with AD and their families
explore and cope with the consequences of such knowledge.
For the free fact sheet, Genetic Counseling: Valuable Information for You and
Your Family, you may write, fax, or e-mail the National Society for Genetic
Counselors (NSGC). Their address is:
NSGC, Executive Office
233 Canterbury Drive
Wallingford, PA 19086-6617
The NSGC does not provide information about specific genetic disorders.
Many questions remain about the usefulness of apoE testing in non-research settings.
Some researchers believe that the best use of apoE testing will be as one in a combination
of methods for assessing patients (including family history, neurological tests, needs
assessments, etc.) to help doctors make informed treatment recommendations.
Experts still do not know how limited information about AD risk can benefit people.
Among the issues are privacy and confidentiality policies related to genetic information
and AD, and the small number of genetic counselors now trained in neurodegenerative
Learning more about the role of apoE in the development of AD may help scientists
identify who would benefit from prevention and treatment efforts. Age, still the most
important known risk factor for AD, continues to be associated with the disease even when
no known genetic factors are present. Research focusing on advancing age may help explain
the role that other genes play in most AD cases. For example, recent research suggests
that certain alleles of other as yet unidentified genes also may increase risk in
Scores of AD researchers are studying the genetics of AD. In addition, researchers,
ethicists, and health care providers are developing policies about the appropriate use of
genetic testing and counseling for AD.
For More Information
Accurate, current information about AD and its risk factors is important to patients
and their families, health professionals, and the public. The Alzheimer's Disease
Education and Referral (ADEAR) Center is a service of the NIA and is funded by the Federal
Government. The ADEAR Center offers information and publications about diagnosis,
treatment, patient care, caregiver needs, long-term care, education and training, and
research related to AD. Staff respond to telephone and written requests and make referrals
to national- and State-level resources.
The ADEAR Center distributes two other free fact sheets about apoE and heredity:
- Alzheimer's Disease and Apolipoprotein E
From the University of California, San Diego Alzheimer's Disease Research Center.
Describes the relationship between AD and apoE.
- Alzheimer's Disease and Heredity
From the Alzheimer Society of Canada. Discusses current knowledge about family history and
AD, FAD, sporadic AD, and apoE4; and what scientists are doing to learn more about each.
For more information about genetics and AD, contact:
PO Box 8250
Silver Spring, MD 20907-8250
Alternate forms of the same gene. Two or more alleles can shape each human trait. Each
person receives two alleles, one from each parent. This combination is one factor among
many that influences a variety of processes in the body. On chromosome 19, the
apolipoprotein E (apoE) gene has three common forms or alleles: E2, E3, and E4. Thus, the
possible combinations in one person are E2/2, E2/3, E2/4, E3/3, E3/4, or E4/4.
- ApoE Gene
A gene on chromosome 19 involved in making apoE, a substance that helps carry cholesterol
in the bloodstream. ApoE is considered a "susceptibility" gene for AD and
appears to influence the age of onset of the disease. However, it is not the sole cause of
AD. No cause and effect relationship exists between a person's apoE status and the
development of AD.
Rod-like structures in every cell of the human body. Chromosomes carry genes. All healthy
people have 46 chromosomes in 23 pairs. Usually, people receive one chromosome in each
pair from each parent.
Basic units of heredity that direct almost every aspect of the construction, operation,
and repair of living organisms. Every human cell has from 50,000 to 100,000 genes arranged
like beads on a string (chromosome). Each gene is a set of biochemical instructions that
tells a cell how to assemble one of many different proteins. Each protein has its own
highly specialized role to play in the body.
- Genetic Mutations
Permanent changes to genes. Once such change occurs, it can be passed on to children. The
relatively rare, early-onset familial AD is associated with mutations in genes on
chromosomes 1, 14, and 21.
Cells translate genetic information into specific proteins. Proteins determine the
physical and chemical characteristics of cells and therefore organisms. Proteins are
essential to all life processes.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
National Institutes of Health
National Institute on Aging
Published in August 1997